Renin passes from the kidneys into the blood where it affects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
With compounds such as (with INN name) aliskiren ((2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-nonanamide), a new antihypertensive has been developed which interferes with the renin-angiotensin system at the beginning of angiotensin II biosynthesis.
As the compound comprises 4 chiral carbon atoms, the synthesis of the enantiomerically pure compound is quite demanding. Therefore, amended routes of synthesis that allow for more convenient synthesis of this sophisticated type of molecules are welcome.
Such 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are any of those having renin inhibitory activity and, therefore, pharmaceutical utility and include, e.g., those disclosed in U.S. Pat. No. 5,559,111. So far, various methods of preparing 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are described in the literature.
In EP-A-0678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations.
In WO 02/02508, a multistep manufacturing process to obtain δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides is described, in which the central intermediate is a 2,7-dialkyl-8-aryl-4-octenic acid or a 2,7-dialkyl-8-aryl-4-octenic acid ester. The double bond of this intermediate is simultaneously halogenated in the 4/5 position and hydroxylated in the 4-position via (under) halo-lactonisation conditions. The halolactone is converted to a hydroxy lactone and then the hydroxy group is converted to a leaving group, the leaving group is substituted with azide, the lactone amidated and then the azide is converted into the amine group.
Further processes for the preparation of intermediates to manufacture δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides are described in WO02/092828 pertaining to the preparation of 2-alkyl-5-halogenpent-4-ene carboxylic esters, WO 2001/009079 pertaining to the preparation of 2-alkyl-5-halogenpent-4-ene carboxylic acids, WO 02/08172 pertaining to the preparation of 2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides, WO 02/02500 pertaining to 2-alkyl-3-phenylpropionic acids, and WO02/024878 pertaining to 2-alkyl-3-phenylpropanols.
In EP-A-1215201 an alternative route to obtain δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides is disclosed. In GB-A-0511686.8 yet an alternative route route to obtain δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides is disclosed using a pyrrolidine intermediate.
Although the existing processes may lead to the desired renin inhibitors, in particular the 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, there exists a need to provide an alternative synthetic route to these 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives to ensure its manufacture in a simple and efficient manner.